rs2077606

Variant names:

• chr17-45451927-G-A
• rs2077606
• NM_014798.3:c.2498-1164C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_014798.3(PLEKHM1):​c.2498-1164C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.128 in 152,308 control chromosomes in the GnomAD database, including 1,584 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.13 (1584 hom., cov: 29)
• Consequence: PLEKHM1 NM_014798.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0250
• Publications: 25 publications found

Genes affected

PLEKHM1 (HGNC:29017): (pleckstrin homology and RUN domain containing M1) The protein encoded by this gene is essential for bone resorption, and may play a critical role in vesicular transport in the osteoclast. Mutations in this gene are associated with autosomal recessive osteopetrosis type 6 (OPTB6). Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Sep 2009]

PLEKHM1 Gene-Disease associations (from GenCC):

• autosomal recessive osteopetrosis 6

  Inheritance: AR Classification: MODERATE, SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, ClinGen, Orphanet
• osteopetrosis, autosomal dominant 3

  Inheritance: AD, Unknown Classification: LIMITED Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.177 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014798.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLEKHM1	NM_014798.3	MANE Select	c.2498-1164C>T		intron	N/A	NP_055613.1	Q9Y4G2
	PLEKHM1	NR_027774.2		n.2361-1164C>T		intron	N/A
	PLEKHM1	NR_027782.2		n.2224-1164C>T		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLEKHM1	ENST00000430334.8	TSL:1 MANE Select	c.2498-1164C>T		intron	N/A	ENSP00000389913.3	Q9Y4G2
	PLEKHM1	ENST00000581448.5	TSL:1	n.*1105-1164C>T		intron	N/A	ENSP00000462160.1	J3KRU0
	PLEKHM1	ENST00000446609.7	TSL:5	c.2498-1164C>T		intron	N/A	ENSP00000394344.3	Q9Y4G2

Frequencies

GnomAD3 genomes AF: 0.128 AC: 19441 AN: 152190 Hom.: 1586 Cov.: 29

Gnomad AFR AF: 0.0596

Gnomad AMI AF: 0.304

Gnomad AMR AF: 0.168

Gnomad ASJ AF: 0.210

Gnomad EAS AF: 0.00135

Gnomad SAS AF: 0.0602

Gnomad FIN AF: 0.0415

Gnomad MID AF: 0.215

Gnomad NFE AF: 0.180

Gnomad OTH AF: 0.174

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.128 AC: 19437 AN: 152308 Hom.: 1584 Cov.: 29 AF XY: 0.120 AC XY: 8920 AN XY: 74482

African (AFR) AF: 0.0597 AC: 2480 AN: 41570

American (AMR) AF: 0.168 AC: 2573 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.210 AC: 730 AN: 3472

East Asian (EAS) AF: 0.00135 AC: 7 AN: 5190

South Asian (SAS) AF: 0.0598 AC: 289 AN: 4832

European-Finnish (FIN) AF: 0.0415 AC: 441 AN: 10626

Middle Eastern (MID) AF: 0.211 AC: 62 AN: 294

European-Non Finnish (NFE) AF: 0.180 AC: 12216 AN: 68000

Other (OTH) AF: 0.171 AC: 362 AN: 2114

Alfa AF: 0.157 Hom.: 839

Bravo AF: 0.136

Asia WGS AF: 0.0270 AC: 94 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	11
DANN	Benign	0.88
PhyloP100		0.025
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2077606; hg19: chr17-43529293;